Glucokinase (GK) is one of four hexokinases that are found in mammals [Colowick, S. P., in The Enzymes, Vol. 9 (P. Boyer, ed.) Academic Press, New York, N.Y., pages 1-48, 1973]. The hexokinases catalyze the first step in the metabolism of glucose, i.e., the conversion of glucose to glucose-6-phosphate. Glucokinase has a limited cellular distribution, being found principally in pancreatic xcex2-cells and liver parenchymal cells. In addition, GK is a rate-controlling enzyme for glucose metabolism in these two cell types that are known to play critical roles in whole-body glucose homeostasis [Chipkin, S. R., Kelly, K. L., and Ruderman, N. B; in Joslin""s Diabetes (C. R. Khan and G. C. Wier, eds.), Lea and Febiger, Philadelphia, Pa., pages 97-115, 1994]. The concentration of glucose at which GK demonstrates half-maximal activity is approximately 8 mM. The other three hexokinases are saturated with glucose at much lower concentrations ( less than 1 mM). Therefore, the flux of glucose through the GK pathway rises as the concentration of glucose in the blood increases from fasting (5 mM) to postprandial (≈10-15 mM) levels following a carbohydrate-containing meal [Printz, R. G., Magnuson, M. A., and Granner, D. K. in Ann. Rev. Nutrition Vol. 13 (R. E. Olson, D. M. Bier, and D. B. McCormick, eds.), Annual Review, Inc., Palo Alto, Calif., pages 463-496, 1993]. These, findings contributed over a decade ago to the hypothesis that GK functions as a glucose sensor in xcex2-cells and hepatocytes (Meglasson, M. D. and Matschinsky, F. M. Amer. J. Physiol. 246, E1-E13, 1984). In recent years, studies in transgenic animals have confirmed that GK does indeed play a critical role in whole-body glucose homeostasis. Animals that do not express GK die within days of birth with severe diabetes while animals overexpressing GK have improved glucose tolerance (Grupe, A., Hultgren, B., Ryan, A. et al., Cell 83, 69-78, 1995; Ferrie, T., Riu, E., Bosch, F. et al., FASEB J., 10, 1213-1218, 1996). An increase in glucose exposure is coupled through GK in xcex2-cells to increased insulin secretion and in hepatocytes to increased glycogen deposition and perhaps decreased glucose production.
The finding that type II maturity-onset diabetes of the young (MODY-2) is caused by loss of function mutations in the GK gene suggests that GK also functions as a glucose sensor in humans (Liang, Y., Kesavan, P., Wang, L. et al., Biochem. J. 309, 167-173, 1995). Additional evidence supporting an important role for GK in the regulation of glucose metabolism in humans was provided by the identification of patients that express a mutant form of GK with increased enzymatic activity. These patients exhibit a fasting hypoglycemia associated with an inappropriately elevated level of plasma insulin (Glaser, B., Kesavan, P., Heyman, M. et al., New England J. Med. 338, 226-230, 1998). While mutations of the GK gene are not found in the majority of patients with type II diabetes, compounds that activate GK and, thereby, increase the sensitivity of the GK sensor system will still be useful in the treatment of the hyperglycemia characteristic of all type II diabetes. Glucokinase activators will increase the flux of glucose metabolism in xcex2-cells and hepatocytes, which will be coupled to increased insulin secretion. Such agents would be useful for treating type II diabetes.
This invention provides a compound, comprising an amide of the formula: 
wherein R1 and R2 are independently hydrogen, halo, amino, hydroxyamino, cyano, nitro, lower alkyl, xe2x80x94OR5, xe2x80x94C(O)OR6, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfonyl, lower alkoxy lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, lower alkyl sulfinyl, or sulfonamido; R3 is cycloalkyl having from 3 to 7 carbon atoms or lower alkyl having from 2 to 4 carbon atoms; R4 is an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, perfluoro-lower alkyl; oxo, xe2x80x94(CH2)nxe2x80x94OR7, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94OR7, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NHxe2x80x94R7, xe2x80x94C(O)C(O)xe2x80x94OR7, or xe2x80x94(CH2)nxe2x80x94NHR7; n is 0, 1, 2, 3 or 4; R5 is hydrogen, lower alkyl, or perfluoro-lower alkyl; R6 is lower alkyl; and R7 is hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof.
The compounds of formula I have been found to activate glucokinase in vitro. Glucokinase activators are useful for increasing insulin secretion in the treatment of type II diabetes.
This invention provides a compound, comprising an amide of the formula: 
wherein R1 and R2 are independently hydrogen, halo, amino, hydroxyamino, cyano, nitro, lower alkyl, xe2x80x94OR5, xe2x80x94C(O)OR6, perfluoro-lower alkyl, lower alkyl thio, perfluoro-lower alkyl thio, lower alkyl sulfinyl, lower alkyl sulfonyl ring, lower alkoxy lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, or sulfonamido; R3 is preferably cycloalkyl having from 3 to 7 carbon atoms atoms but also includes lower alkyl having from 2 to 4 carbon atoms, R4 is an unsubstituted or mono-substituted five or six -membered heteroaromatic connected by a ring carbon atom to the amine group shown, which five- or six-membered heteroaromatic ring contains from 1 to 3 heteroatoms selected from sulfur, oxygen or nitrogen, with one heteroatom being nitrogen which is adjacent to the connecting ring carbon atom; said mono-substituted heteroaromatic ring being monosubstituted at a position on a ring carbon atom other than adjacent to said connecting carbon atom with a substituent selected from the group consisting of lower alkyl, halo, nitro, cyano, perfluoro-lower alkyl; oxo, xe2x80x94(CH2)nxe2x80x94OR7, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94OR7, xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NHxe2x80x94R7, xe2x80x94C(O)C(O)xe2x80x94OR7, or xe2x80x94(CH2)nxe2x80x94NHR7; n is 0, 1, 2, 3 or 4; R5 is hydrogen, lower alkyl, or perfluoro-lower alkyl; R6 is lower alkyl; and R7 is hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof.
In the compound of formula I, the xe2x80x9c.xe2x80x9d illustrates the asymmetric carbon atom in this compound. The compound of formula I may be present either as a racemate or in the xe2x80x9cRxe2x80x9d configuration at the asymmetric carbon shown. The xe2x80x9cRxe2x80x9d enantiomers are preferred.
As used throughout this application, the term xe2x80x9clower alkylxe2x80x9d includes both straight chain and branched chain alkyl groups having from 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, preferably methyl and ethyl. As used herein, the term xe2x80x9chalogenxe2x80x9d is used interchangeably with the word xe2x80x9chaloxe2x80x9d, and, unless otherwise stated, designates all four halogens, i.e. fluorine, chlorine, bromine, and iodine. As used herein, xe2x80x9cperfluoro-lower alkylxe2x80x9d means any lower alkyl group wherein all of the hydrogens of the lower alkyl group are substituted or replaced by fluoro. Among the preferred perfluoro-lower alkyl groups are trifluoromethyl, pentafluoroethyl, heptafluoropropyl, etc.
As used herein, the term xe2x80x9clower alkoxyxe2x80x9d signifies a lower alkyl group as defined above linked via an oxygen to the remainder of the molecule and includes both straight chain and branched chain alkoxy groups having from 1 to 7 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, preferably methoxy and ethoxy. xe2x80x9cLower alkoxy lower alkylxe2x80x9d signifies a lower alkoxy linked via an oxygen to a lower alkyl group, which is linked to the remainder of the molecule.
As used herein the term xe2x80x9carylxe2x80x9d signifies aryl mononuclear aromatic hydrocarbon groups such as phenyl, tolyl, etc. which can be unsubstituted or substituted in one or more positions with halogen, nitro, lower alkyl, or lower alkoxy substituents and polynuclear aryl groups, such as naphthyl, anthryl, and phenanthryl, which can be unsubstituted or substituted with one or more of the aforementioned groups. Preferred aryl groups are the substituted and unsubstituted mononuclear aryl groups, particularly phenyl. The term xe2x80x9carylalkylxe2x80x9d denotes an alkyl group, preferably lower alkyl, in which one of the hydrogen atoms can be replaced by an aryl group. Examples of arylalkyl groups are benzyl, 2-phenylethyl, 3-phenylpropyl, 4-chlorobenzyl, 4-methoxybenzyl and the like.
As used herein, the term xe2x80x9clower alkanoic acidxe2x80x9d denotes lower alkanoic acids containing from 2 to 7 carbon atoms such as propionic acid, acetic acid and the like. The term xe2x80x9clower alkanoylxe2x80x9d denotes monovalent alkanoyl groups having from 2 to 7 carbon atoms such as propionyl, acetyl and the like. The term xe2x80x9caroic acidsxe2x80x9d denotes aryl alkanoic acids where aryl is as defined above and alkanoic contains from 1 to 6 carbon atoms. The term xe2x80x9caroylxe2x80x9d denotes aroic acids wherein aryl is as defined hereinbefore, with the hydroxide group of the COOH moiety removed. Among the preferred aroyl groups is benzoyl.
As used herein, xe2x80x94(O)OR6 represents 
and so forth.
The heteroaromatic ring defined by R4 can be an unsubstituted or mono-substituted five- or six-membered heteroaromatic ring having from 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, or sulfur and connected by a ring carbon to the amine of the amide group shown. The heteroaromatic ring contains a first nitrogen heteroatom adjacent to the connecting ring carbon atom and if present, the other heteroatoms can be sulfur, oxygen or nitrogen. Such heteroaromatic rings include, for example, pyrazinyl, pyridazinyl, isoxazolyl, isothiazolyl, and pyrazolyl. Among the preferred heteroaromatic rings are included pyridinyl, pyrimidinyl, pyrazinyl, thiazolyl, oxazolyl, and imidazolyl. These heteroaromatic rings which constitute R4 are connected via a ring carbon atom to the amide group to form the amides of formula I. The ring carbon atom of the heteroaromatic ring which is connected via the amide linkage to form the compound of formula I cannot contain any substituent.
When R4 is an unsubstituted or mono-substituted five-membered heteroaromatic ring, the preferred rings are those which contain a nitrogen heteroatom adjacent to the connecting ring carbon and a second heteroatom adjacent to the connecting ring carbon.
The preferred five-membered heteroaromatic rings contain 2 or 3 heteroatom with thiazolyl, imidazolyl, oxazolyl and thiadiazolyl being especially present. When the heteroaromatic ring is a six-membered heteroaromatic ring, the ring is connected by a ring carbon to the amine group shown, with one nitrogen heteroatom being adjacent to the connecting ring carbon atom. The preferred six-membered heteroaromatic rings include, for example, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, and triazinyl.
The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d as used herein include any salt with both inorganic or organic pharmaceutically acceptable acids such as hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, maleic acid, acetic acid, succinic acid, tartaric acid, methanesulfonic acid, para-toluene sulfonic acid and the like. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d also includes any pharmaceutically acceptable base salt such as amine salts, trialkyl amine salts and the like. Such salts can be formed quite readily by those skilled in the art using standard techniques.
During the course of the reactions provided below in the Reaction Scheme and discussion, the various functional groups such as the free carboxylic acid or hydroxy groups may be protected via conventional hydrolyzable ester or ether protecting groups. As used herein, the term xe2x80x9chydrolyzable ester or ether protecting groupsxe2x80x9d designates any ester or ether conventionally used for protecting carboxylic acids or alcohols which can be hydrolyzed to yield the respective carboxyl or hydroxyl group. Exemplary ester groups useful for those purposes are those in which the acyl moieties are derived from a lower alkanoic, aryl lower alkanoic, or lower alkane dicarboxylic acid. Among the activated acids which can be utilized to form such groups are acid anhydrides, acid halides, preferably acid chlorides or acid bromides derived from aryl or lower alkanoic acids. Examples of anhydrides are anhydrides derived from monocarboxylic acid such as acetic anhydride, benzoic acid anhydride, and lower alkane dicarboxylic acid anhydrides, e.g. succinic anhydride as well as chloro formates e.g. trichloro, ethylchloro formate being preferred. A suitable ether protecting group for alcohols are, for example, the tetrahydropyranyl ethers such as 4-methoxy-5,6-dihydroxy-2H-pyranyl ethers. Others are aroylmethylethers such as benzyl, benzhydryl or trityl ethers or xcex1-lower alkoxy lower alkyl ethers, for example, methoxymethyl or allylic ethers or alkyl silylethers such as trimethylsilylether.
Similarly, the term xe2x80x9camino protecting groupxe2x80x9d designates any conventional amino protecting group which can be cleaved to yield the free amino group. The preferred protecting groups are the conventional amino protecting groups utilized in peptide synthesis. Especially preferred are those amino protecting groups which are cleavable under mildly acidic conditions from about pH 2 to 3. Particularly preferred amino protecting groups are t-butyl carbamate (BOC), benzyl carbamate (CBZ), and 9-fluorenylmethyl carbamate (FMOC).
In accordance with one embodiment of this invention, R3 is cyclopentyl (the compound I-D). The embodiments of the compound I-D are those compounds where R4 is an unsubstituted thiazole (Compound I-D1). Among the various embodiments of the compound of I-D1 are included those compounds where:
a) one of R1 and R2 is hydrogen, halo, perfluoro-lower alkyl and the other of said R1 and R2 is halo, nitro, or perfluoro-lower alkyl;
b) one of R1 and R2 is amino, halo, nitro or hydrogen and the other of said R1 and R2 is amino, cyano or nitro;
c) one of R1 and R2 is lower alkylthio, perfluoro-lower alkyl thio, halo or hydrogen and the other of said R1 and R2 is perfluoro-lower alkylthio, lower alkylsulfinyl or lower alkylthio;
d) one of R1 and R2 is lower alkyl sulfonyl, hydrogen, nitro, cyano, amino, hydroxyamino, sulfonamido or halo, and the other of said R1 and R2 is lower alkyl sulfonyl;
e) one of R1 and R2 is lower alkyl sulfonyl, and the other of said R1 and R2 is halo or perfluoro-lower alkyl;
f) one of R1 and R2 is perfluoro-lower alkyl sulfonyl or hydrogen and the other of said R1 and R2 is perfluoro-lower alkyl sulfonyl;
g) one of R1 and R2 is xe2x80x94OR5, or xe2x80x94C(O)xe2x80x94OR6 and the other of said R1 and R2 is hydrogen or xe2x80x94OR5; and R5 and R6 are as above
h) one of R1 and R2 is xe2x80x94OR5 and the other is halo, and
i) one of R1 and R2 is hydrogen (preferably R1) and the other of said R1 and R2 is lower alkoxy lower alkyl sulfonyl (preferably R2).
In accordance with another embodiment of this invention where R3 is cyclopentyl, the embodiments are those compounds where R4 is a mono-substituted thiazole (compounds I-D2). Among the embodiments of compounds I-D2, are those compounds where the mono-substitution is xe2x80x94(CH2)nxe2x80x94OR7 and n and R7 are as above (compounds I-D2(a)). Among the embodiments of compounds I-D2 (a) are those compounds where:
a) one of R1 and R2 is halo and the other of said R1 and R2 is hydrogen or halo;
b) one of R1 and R2 is lower alkyl sulfonyl, and the other of said R1 and R2 is lower alkyl sulfonyl or hydrogen; and
c) one of R1 and R2 is hydrogen and the other of said R1 and R2 is lower alkyl or perfluoro-lower alkyl.
In accordance with another embodiment of the invention where R3 is cyclopentyl and R4 is a mono-substituted thiazole (Compounds I-D2), are those compounds where the mono-substitution is lower alkyl. Among the embodiments of these compounds are compounds where:
a) one of R1 and R2 is hydrogen or halo and the other of R1 and R2 is halo;
b) one of R1 and R2 is lower alkyl sulfonyl and the other of R1 and R2 is hydrogen or halo.
Among another embodiment of the compounds I-D are those compounds where the mono-substituted thiazole is substituted with xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94OR7 wherein n is 0 or 1 and R7 is hydrogen, or lower alkyl (Compounds I-D2(c)). Among the embodiments of compounds of formula I-D2(c) are those compounds where:
a) one of R1 and R2 is hydrogen and the other of said R1 and R2 is halo;
b) R1 and R2 are each independently halo;
c) one of R1 and R2 is halo and the other of said R1 and R2 is perfluoro-lower alkyl;
d) one of R1 or R2 is nitro, amino or hydrogen and the other of said R1 and R2 is nitro or amino; and
e) one of R1 and R2 is lower alkyl sulfonyl, perfluoro-lower alkyl, halo or hydrogen and the other of said R1 and R2 is lower alkyl sulfonyl;
f) one of of R1 and R2 is hydrogen, halo or perfluoro-lower alkyl and the other of said R1 and R2 is perfluoro-lower alkyl sulfonyl.
In accordance with another embodiment of this invention, where R3 and cyclopentyl and R4 is a mono-substituted thiazole (Compounds I-D2) are those compounds where the mono-substituted thiazole is substituted with xe2x80x94C(O)xe2x80x94C(O)xe2x80x94OR7 wherein R7 is as above (Compounds I-D2(d)).
Among the embodiments of compound I-D2(d) are those compounds where:
a) one of R1 and R2 are hydrogen and the other of said R1 and R2 is nitro or amino;
b) one of R1 and R2 is halo or perfluoro-lower alkyl and the other of said R1 and R2 is perfluoro-lower alkyl, halo or hydrogen; and
c) one of R1 and R2 is hydrogen or halo and the other of said R1 and R2 is lower alkyl sulfonyl.
In accordance with another embodiment of this invention, where R3 is cyclopentyl and R4 is a mono-substituted thiazole, compounds I-D2, are those compounds where the mono-substitution on the thiazole ring is a nitro group and one of R1 and R2 are hydrogen and halo and the other of R1 and R2 is halo or lower alkyl sulfonyl, or R1 and R2 are each independently halo (compound of formula I-D2(e)).
In accordance with another embodiment of this invention, where R3 is cyclopentyl and R4 is a mono-substituted thiazole, compounds I-D2, are those compounds where the mono-substitution on the thiazole ring is xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NHxe2x80x94R7 where n and R7 are as in formula I, preferably where one of R1 and R2 is lower alkyl sulfonyl or halo and the other of R1 and R2 is halo or hydrogen.
In accordance with another embodiment of this invention, where R3 is cyclopentyl and R4 is a mono-substituted thiazole, compounds I-D2, are those compounds where the mono-substitution on the thiazole ring is halo, preferably where one of R1 and R2 is hydrogen or halo and the other of R1 and R2 is lower alkyl sulfonyl.
In accordance with another embodiment of this invention, where R3 is cyclopentyl (Compound I-D) and R4 is an unsubstituted pyridine (Compounds I-D3). Among the embodiments of compound I-D3 are those compounds where:
a) one of R1 and R2 is halo and the other of R1 and R2 is lower alkyl sulfonyl;
b) one of R1 and R2 are halo, perfluoro-lower alkyl or hydrogen and the other of said R1 and R2 is halo, perfluoro-lower alkyl, amino, cyano or nitro;
c) one of R1 and R2 is lower alkyl thio, perfluoro-lower alkyl thio or cyano, and the other is hydrogen;
d) one of R1 and R2 is lower alkyl sulfonyl, halo, cyano, nitro or hydrogen and the other of said R1 and R2 is lower alkyl sulfonyl, and
e) one of R1 and R2 is perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl or hydrogen and the other of said R1 and R2 is perfluoro-lower alkyl sulfonyl, or perfluoro-lower alkyl.
In accordance with another embodiment of the invention, where R3 is cyclopentyl (Compounds I-D) are those compounds where R4 is a mono-substituted pyridine ring. Among the embodiments of the mono-substituted pyridine (Compounds I-D4) are those compounds where the mono-substitution is cyano. Among the embodiments of such compounds are those compounds where one of R1 and R2 is perfluoro-lower alkyl or halo and the other of R1 and R2 is lower alkyl thio or halo, especially where R1 and R2 are each independently halo.
In accordance with another embodiment of the invention, where R3 is cyclopentyl (Compounds I-D) are those compounds where R4 is a mono-substituted pyridine ring. Among the embodiments of the mono-substituted pyridine (Compounds I-D4) are those compounds where the mono-substitution is xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94OR7 wherein n and R1 are as above (compound I-D4(a)). Among the embodiments of compounds I-D4(a) are those compounds where:
a) R1 and R2 are each independently halo;
b) one of R1 and R2 is halo or hydrogen and the other of said R1 and R2 is halo, amino, cyano, nitro or perfluoro-lower alkyl; and
c) one of R1 and R2 is perfluoro-lower alkyl sulfonyl, lower alkyl sulfonyl or hydrogen and the other of said R1 and R2 is perfluoro-lower alkyl sulfonyl or lower alkyl sulfonyl.
Other embodiments of the compounds of formula I-D4 are those compounds where the pyridine ring is mono-substituted with xe2x80x94(CH2)nxe2x80x94OR7 wherein n and R7 are as above (Compounds I-D4(b)). Among the embodiments of the compound I-D4(b) are those compounds where:
a) one of R1 and R2 is halo and the other of said R1 and R2 is hydrogen or halo; and
b) one of R1 and R2 is lower alkyl sulfonyl or hydrogen and the other of said R1 and R2 is lower alkyl sulfonyl.
Another embodiment of compounds where R3 is cyclopentyl and R4 is a mono-substituted pyridine ring are those compounds where the pyridine ring is mono-substituted with a halo or perfluoro lower alkyl substituent, the compound of formula I-D4(c). Among the embodiments of the compound of formula I-D4(c) are those compounds where:
a) one of R1 and R2 is halo or perfluoro-lower alkyl and the other of said R1 and R2 is halo, nitro, lower alkyl suffonyl, or lower alkyl thio;
b) one of R1 and R2 is halo or hydrogen and the other of said R1 and R2 is halo; and
c) one of R1 and R2 is halo, nitro or hydrogen and the other of said R1 and R2 is perfluoro-lower alkyl sulfonyl or lower alkyl sulfonyl.
In accordance with another embodiment of this invention are compounds of where R3 is cyclopentyl and R4 is a mono-substituted pyridine are those compounds where the pyridine is mono-substituted with a nitro substituent, (Compound I-D4(d)). The embodiments of the compound I-D4(d) include compounds where one of R1 and R2 is halo and the other of said R1 or R2 is hydrogen, halo, or lower alkyl sulfonyl and compounds where one of R1 and R2 is halo or perfluoro-lower alkyl and the other of said R1 or R2 is halo or lower alkyl thio.
In accordance with another embodiment of this invention are compounds of formula I where R3 is cyclopentyl and R4 is mono-substituted pyridine and the mono-substitution is a lower alkyl group (Compounds I-D4(e)). Among the embodiments of compounds I-D4(e) are those compounds where one of R1 and R2 is halo or hydrogen and the other of said R1 and R2 is halo, perfluoro-lower alkyl, perfluoro-lower alkyl sulfonyl, or lower alkyl sulfonyl, and compounds where one of R1 and R2 is halo and other of said R1 or R2 is lower alkyl sulfonyl.
In accordance with another embodiment of this invention where R3 is cyclopentyl and R4 is a mono-substituted pyridine are those compounds where the mono-substituent is xe2x80x94(CH2)nxe2x80x94C(O)xe2x80x94NHxe2x80x94R7 wherein n and R1 are as above (Compound I-D4(f)). Among the embodiments of compound I-D4(f) are those compounds wherein one of R1 and R2 are independently selected from the group consisting of halo or hydrogen and the other of said R1 and R2 is halo, or lower alkyl sulfonyl, and those compounds where one of R1 and R2 is halo and other of said R1 or R2 is perfluoro-lower alkyl.
Another embodiment of this invention where R3 is cyclopentyl are those compounds where R4 is an unsubstituted imidazolyl (Compound I-D5). Among the embodiments of compounds I-D5 are those compounds wherein one of R1 and R2 is selected from the group consisting of halo and hydrogen and the other of said R1 and R2 is halo, or lower alkyl sulfonyl and those compounds where one of R1 and R2 is lower alkyl sulfonyl and other of said R1 or R2 is nitro or perfluoro-lower alkyl.
Another embodiment of the compounds of this invention are those compounds where R3 is cyclopentyl and R4 is an isoxazolyl ring (the compound I-D6). The embodiments of compound I-D6 are those compounds where the isoxazolyl ring is unsubstituted or substituted, preferably mono-substituted. Among the mono-substituted substituents, the preferred substituents substituted on the isoxazolyl ring is lower alkyl. An embodiment of the compound I-D6, either where the isoxazolyl ring is unsubstituted or substituted with a lower alkyl substituent are those compounds where one of R1 and R2 is halo, nitro, perfluoro-lower alkyl, or lower alkyl sulfonyl and the other of R1 and R2 is hydrogen or halo.
Another embodiment of this invention where R3 is cyclopentyl are those compounds where R4 is either an unsubstituted oxazolyl, or an oxazolyl mono-substituted with a lower alkyl group. Another embodiment with respect to either of those compounds are those compounds where one of R1 or R2 is halo, nitro or perfluoro-lower alkyl, or lower alkyl sulfonyl and the other is of R1 or R2 is hydrogen or halo.
Another embodiment of this invention where R3 is cyclopentyl are those compounds where R4 is pyridazinyl which is either unsubstituted or substituted with a lower alkyl group (Compound I-D7). Embodiments of the compound I-D7 are encompassed by this invention include those compounds where one of R1 or R2 is halo, nitro or perfluoro-lower alkyl, or lower alkyl sulfonyl and the other of said R1 or R2 is hydrogen or halo.
Another embodiment of this invention where R3 is cyclopentyl include compounds where R4 is unsubstituted pyrimidinyl. The embodiments of those compounds where R3 is cyclopentyl and R4 is unsubstituted pyrimidinyl include those compounds where one of R1 or R2 is halo, nitro, perfluoro-lower alkyl, or lower alkyl sulfonyl and the other is hydrogen or halo and those compounds where one of R1 and R2 is lower alkyl sulfonyl and other of said R1 or R2 is cyano, nitro, or perfluoro-lower alkyl.
In accordance with another embodiment of the invention, where R3 is cyclopentyl (Compounds I-D) are those compounds where R4 is a mono-substituted pyrimidine ring. Among the embodiments of the mono-substituted pyrimidine are those compounds where the mono-substitution is lower alkyl. Among the embodiments of such compounds are those compounds where:
a) one of R1 and R2 is perfluoro-lower alkyl and the other of said R1 and R2 is hydrogen;
b) one of R1 and R2 is lower alkyl sulfonyl and the other of said R1 and R2 is cyano or nitro; and
c) one of R1 and R2 is lower alkyl sulfonyl and the other of said R1 and R2 is perfluoro-lower alkyl,
d) one of R1 and R2 is lower alkyl sulfonyl and the other of said R1 and R2 is halo.
In accordance with yet another embodiment of the invention, where R3 is cyclopentyl (Compounds I-D) are those compounds where R4 is a mono-substituted dihydro pyrimidine ring. Among the embodiments of the mono-substituted pyrimidine are those compounds where the mono-substitution is oxo. Among the embodiments of such compounds are those compounds where one of R1 and R2 is lower alkyl sulfonyl and the other of said R1 and R2 is halo, nitro, or perfluoro-lower alkyl.
Another embodiment of this invention includes compounds where R3 is cyclopentyl where R4 is an unsubstituted thiadiazolyl ring. Among the embodiments included within those compounds where R3 is cyclopentyl and R4 is an unsubstituted thiadiazolyl ring are those compounds wherein one of R1 or R2 is halo, nitro or perfluoro-lower alkyl, or lower alkyl sulfonyl and the other of said R1 and R2 is hydrogen or halo.
In accordance with other embodiments of this invention, R3 in the compound of formula I can be cycloheptyl or cyclohexyl. The embodiments of the compound of formula I where R3 is cycloheptyl or cyclohexyl include those compounds where R4 is thiazolyl which can be mono-substituted or unsubstituted. Embodiments included within such compounds where R3 is cycloheptyl or cyclohexyl and R4 is an unsubstituted thiazolyl include those compounds wherein one of R1 and R2 is halo, lower alkyl sulfonyl, perfluoro-lower alkyl sulfonyl, perfluoro-lower alkyl, and the other is of said R1 and R2 is halo, perfluoro-lower alkyl or hydrogen.
In accordance with another embodiment of this invention, R3 is cyclopentyl (Compound I-D) and R4 is an unsubstituted pyrazinyl. Among the embodiments of such compounds are those compounds where:
a) one of R1 and R2 is lower alkyl sulfonyl, halo, or perfluoro-lower alkyl and the other of R1 and R2 is hydrogen, halo, cyano, nitro, or perfluoro-lower alkyl;
b) one of R1 and R2 is perfluoro-lower alkyl or lower alkyl sulfonyl and the other of said R1 and R2 is hydrogen, cyano or nitro;
c) one of R1 and R2 is lower alkyl sulfonyl and the other is perfluoro-lower alkyl or halo.
In accordance with yet another embodiment of the invention, where R3 is cyclopentyl (Compounds I-D) are those compounds where R4 is unsubstituted triazinyl. Among the embodiments of such compounds are those compounds where R1 and R2 are each independently halo.
The compound of formula I can be prepared starting from the compound of formula V by the following Reaction Scheme: 
wherein R1, R2, R3 and R4 are as above and R15 is hydrogen or lower alkyl.
The carboxylic acids or their lower alkyl esters of formula V wherein one of R1 and R2 is nitro, cyano, thiol, thiomethyl, methylsulfonyl, amino, chloro, bromo, or iodo and the other is hydrogen are commercially available. In cases where only the carboxylic acids are available, they can be converted to the corresponding esters of lower alkyl alcohols using any conventional esterification methods. All the reactions hereto forward are to be carried out on lower alkyl esters of the carboxylic acids of formula V, or may be carried out on the carboxylic acids themselves. The amino substituted compounds of formula V can be converted to other substituents either before or after conversion to the compounds of formula 1-axe2x80x2. In this respect, the amino groups can be diazotized to yield the corresponding diazonium compound, which in situ can be reacted with the desired lower alkyl thiol, perfluoro-lower alkyl thiol (see for example, Baleja, J. D. Synth. Comm. 1984, 14, 215; Giam, C. S.; Kikukawa, K., J. Chem. Soc, Chem. Comm. 1980, 756; Kau, D.; Krushniski, J. H.; Robertson, D. W, J. Labelled Compd Rad. 1985, 22, 1045; Oade, S.; Shinhama, K.; Kim, Y. H., Bull Chem Soc. Jpn. 1980, 53, 2023; Baker, B. R.; et al, J. Org. Chem. 1952, 17, 164) to yield corresponding compounds of formula V where one of the substituents is lower alkyl thio, perfluoro-lower alkyl thio and the other is hydrogen. If desired, the lower alkyl thio or perfluoro-lower alkyl thio compounds can then be converted to the corresponding lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl substituted compounds of formula V by oxidation. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion. If it is desired to produce compounds of lower alkyl or perfluoro-lower alkyl groups of compounds of formula V, the corresponding halo substituted compounds of formula V can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding alkyl group (see for example, Katayama, T.; Umeno, M., Chem. Lett. 1991, 2073; Reddy, G. S.; Tam., Organometallics, 1984, 3, 630; Novak, J.; Salemink, C. A., Synthesis, 1983, 7, 597; Eapen, K. C.; Dua, S. S.; Tamboroski, C., J. Org. Chem. 1984, 49, 478; Chen, Q.-Y.; Duan, J.-X. J. Chem. Soc. Chem. Comm. 1993, 1389; Clark, J. H.; McClinton, M. A.; Jone, C. W.; Landon, P.; Bisohp, D.; Blade, R. J., Tetrahedron Lett. 1989, 2133; Powell, R. L.; Heaton, C. A, U.S. Pat. No. 5,113,013) can be utilized to effect this conversion. On the other hand, the thio substituent can be oxidized to a xe2x80x94SO3H group which then can be converted to xe2x80x94SO2Cl which is reacted with ammonia to form the sulfonamide substituent xe2x80x94S(O)2xe2x80x94NH2.
For compounds of formula V where one of R1 and R2 is hydrogen and the other is lower alkoxy lower alkyl sulfonyl, the corresponding thiol compound may be used as a starting material. The compound of formula V where one of R1 and R2 is hydrogen and the other is thiol may be alkoxylated by conventional methods (for example with alkoxy alkyl halide) to the corresponding lower alkoxy lower alkyl sulfanyl of formula V, which is then hydrolyzed by conventional methods (for example with lithium hydroxide, water, and tetrahydrofuran or sodium hydroxide and methanol) to the corresponding carboxylic acid. The latter is alkylated by conventional methods to add the desired methyl-cycloalkyl R3 substituent. The resulting compound is oxidized by conventional methods at the sulfanyl to provide lower alkoxy lower alkyl sulfonyl compound of formula XII. Conversion of the compound of formula XII to a compound of formula I-axe2x80x2 is described below.
For compounds of formula V wherein one or both of R1 and R2 is hydroxyamino, the corresponding nitro compounds can be used as starting material and can be converted to the corresponding compounds where R1 and/or R2 are hydroxyamino. Any conventional method of converting a nitro group to the corresponding aromatic hydroxyamino compound can be used to affect this conversion.
The carboxylic acids or esters of formula V wherein both of R1 and R2 are chloro, or fluoro are commercially available. In cases, where only the carboxylic acids are available, they can converted to the corresponding esters of lower alkyl alcohols using any conventional esterification method. To produce the compound of formula V where both R1 and R2 are nitro, 3,4-dinitrotoluene can be used as starting material. This compound can be converted to the corresponding 3,4-dinitrophenyl acetic acid. This conversion can take place either before or after the compound of formula V is converted to the compound of formula I-axe2x80x2. Any conventional method of converting an aryl methyl group to the corresponding aryl acetic acid can be utilized to effect this conversion (see for example, Clark, R. D.; Muchowski, J. M.; Fisher, L. E.; Flippin, L. A.; Repke, D. B.; Souchet, M, Synthesis, 1991, 871). The compounds of formula V where both R1 and R2 substituents are amino can be obtained from the corresponding dinitro compound of formula V, described above. Any conventional method of reducing a nitro group to an amine can be utilized to effect this conversion. The compound of formula V where both R1 and R2 are amine groups can be used to prepare the corresponding compound of formula V where both R1 and R2 are iodine or bromine via a diazotization reaction. Any conventional method of converting amino group to an iodo or bromo group (see for example, Lucas, H. J.; Kennedy, E. R. Org. Synth. Coll. Vol, II 1943, 351) can be utilized to effect this conversion. If it is desired to produce compounds of formula V where both R1 and R2 are lower alkyl thio or perfluoro-lower alkyl thio groups, the compound of formula V where R1 and R2 are amino can be used as starting material. Any conventional method of converting aryl amino group to aryl thioalkyl group can be utilized to effect this conversion. If it is desired to produce compound of formula V where R1 and R2 are lower alkyl sulfonyl or lower perfluoro alkyl sulfonyl, the corresponding compounds of formula V where R1 and R2 are lower alkyl thio or perfluoro-lower alkyl thio can be used as starting material. Any conventional method of oxidizing alkyl thio substituents to sulfones can be utilized to effect this conversion. If it is desired to produce compounds of formula V where both R1 and R2 are substituted with lower alkyl or perfluoro-lower alkyl groups, the corresponding halo substituted compounds of formula V can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding alkyl or perfluoro-lower alkyl group can be utilized to effect this conversion.
The carboxylic acids corresponding to the compounds of formula V where one of R1 and R2 is nitro and the other is halo are known from the literature (see for 4-chloro-3-nitrophenyl acetic acid, Tadayuki, S.; Hiroki, M.; Shinji, U.; Mitsuhiro, S. Japanese patent, JP 71-99504, Chemical Abstracts 80:59716; see for 4-nitro-3-chlorophenyl acetic acid, Zhu, J.; Beugelmans, R.; Bourdet, S.; Chastanet, J.; Rousssi, G. J. Org. Chem. 1995, 60, 6389; Beugelmans, R.; Bourdet, S.; Zhu, J. Tetrahedron Lett. 1995, 36, 1279). These carboxylic acids can be converted to the corresponding lower alkyl esters using any conventional esterification methods. Thus, if it is desired to produce the compound of formula V where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is nitro and the other is chloro can be used as starting material. In this reaction, any conventional method of nucleophilic displacement of aromatic chlorine group with a lower alkyl thiol can be used (see for example, Singh, P.; Batra, M. S.; Singh, H, J. Chem. Res.-S 1985 (6), S204; Ono, M.; Nakamura, Y.; Sata, S.; Itoh, I, Chem. Lett, 1988, 1393; Wohrle, D.; Eskes, M.; Shigehara, K.; Yamada, A, Synthesis, 1993, 194; Sutter, M.; Kunz, W, U.S. Pat. No. 5,169,951). Once the compounds of formula V where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio are available, they can be converted to the corresponding compounds of formula V where one of R1 and R2 is nitro and the other is lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl using conventional oxidation procedures. If it is desired to produce compounds of formula V where one of R1 and R2 is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is nitro and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of reducing an aromatic nitro group to an amine can be utilized to effect this conversion. If it is desired to produce compounds of formula V where one of R1 and R2 is lower alkyl thio and the other is perfluoro-lower alkyl thio, the corresponding compound where one of R1 and R2 is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of diazotizing aromatic amino group and reacting it in situ with the desired lower alkyl thiol can be utilized to effect this conversion. If it is desired to produce compounds of formula V where one of R1 and R2 is lower alkyl sulfonyl and the other is perfluoro-lower alkyl sulfonyl, the corresponding compounds where one of R1 and R2 is lower alkyl thio and the other is perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of oxidizing an aromatic thio ether group to the corresponding sulfone group can be utilized to effect this conversion. If it is desired to produce compounds of formula V where one of R1 and R2 is halo and the other is lower alkyl thio or perfluoro-lower alkyl thio, the corresponding compounds where one of R1 and R2 is amino and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of diazotizing an aromatic amino group and conversion of it in situ to an aromatic halide can be utilized to effect this conversion. If it is desired to produce compounds of formula V where one of R1 and R2 is halo and the other is lower alkyl sulfonyl or perfluoro-lower alkyl sulfonyl, the corresponding compounds where one of R1 and R2 is halo and the other is lower alkyl thio or perfluoro-lower alkyl thio can be used as starting materials. Any conventional method of oxidizing an aromatic thio ether to the corresponding sulfone can be utilized to effect this conversion. If it is desired to produce compounds of various combinations of lower alkyl and perfluoro-lower alkyl groups of compounds of formula V, the corresponding halo substituted compounds of formula V can be used as starting materials. Any conventional method of converting an aromatic halo group to the corresponding alkyl group can be utilized to effect this conversion. If one wishes to prepare the compound formula V where one of R1 and R2 is nitro and the other is amino, the compound of formula V where one of R1 and R2 is nitro and other is chloro can be used as a starting material. The chloro substituent on the phenyl ring can be converted to an iodo substituent (see for example, Bunnett, J. F.; Conner, R. M.; Org. Synth. Coll Vol V, 1973, 478; Clark, J. H.; Jones, C. W. J. Chem. Soc. Chem. Commun. 1987, 1409), which in turn can be reacted with an azide transferring agent to form the corresponding azide (see for example, Suzuki, H.; Miyoshi, K.; Shinoda, M. Bull. Chem. Soc. Jpn, 1980, 53, 1765). This azide can then be reduced in a conventional manner to form the amine substituent by reducing it with commonly used reducing agent for converting azides to amines (see for example, Soai, K.; Yokoyama, S.; Ookawa, A. Synthesis, 1987, 48).
If it is desired to produce the compound of formula V where both R1 and R2 are cyano, this compound can be prepared as described hereinbefore from compounds where R1 and R2 are amino via diazotization to produce the diazonium salt followed by reaction with cyano group transferring agent. If it is desired to convert the commercially available compound to the compound of formula V where one of R1 and R2 is cyano and the other is not cyano, the compound of formula V where one of R1 and R2 is nitro and the other is chloro is used as a starting material. Using this starting material, the nitro is converted to the cyano and the halo is converted to any other desired R1 and R2 substituent as described hereinbefore.
If it is desired to produce the compound of formula V where both R1 and R2 are lower alkoxy lower alkyl sulfonyl, the compound of formula V where both R1 and R2 are amino can be used as starting material. Any conventional method of converting an aryl amino group to an aryl thio group may be utilized to effect this conversion. The thio groups can then be converted to lower alkoxy lower alkyl sulfonyl groups as described above.
If it is desired to produce the compound of formula V wherein one of R1 or R2 is a xe2x80x94C(O)xe2x80x94OR6, this compound can be formed from the corresponding compound where R1 and R2 is an amino group by converting the amino group to a diazonium salt, reacting the diazonium salt with a hydrohalic acid to form the corresponding halide, and then reacting this halide with a Grignard reagent to produce the corresponding acid which can be esterified. On the other hand, if one wants to produce the compound of formula V where both R1 and R2 are carboxylic acid groups, this compound can be produced as described above from the corresponding compound of formula V where both R1 and R2 are amino groups. In the same manner, the amino groups in the compound of formula V can be converted to the corresponding compound where R1 or R2 or both of R1 and R2 is OR5 by simply reacting the amino group with sodium nitrate in sulfuric acid to convert the amino group to a hydroxy group and thereafter etherifying, if desired, the hydroxy group.
The substituents which form R1 and R2 can be added to the ring after condensation after the compound of formula XII with the compound of formula VIII to form the compound of formula I-axe2x80x2. Hence, all of the reactions described to produce various substituents of R1 and R2 in the compound of formula I can be carried out on the compound of formula I-axe2x80x2 after its formation by the reaction of compound of formula XII and VIII to form the compound of formula I-axe2x80x2.
In the first step of this Reaction Scheme, the alkyl halide of formula VI is reacted with the compound of formula V, to produce the compound of formula VII. In this reaction, if in the compounds of formula V, R1 or R2 is an amino group, such amino group(s) have to be protected before carrying out the alkylation reaction with the alkyl halide of formula VI. The amino group can be protected with any conventional acid removable group (see for example, for t-butyloxycarbonyl group see, Bodanszky, M. Principles of Peptide Chemistry, Springer-Verlag, New York, 1984, p 99). The protecting group has to be removed from the amino groups after preparing the corresponding amine protected compounds of formula I-axe2x80x2 to obtain the corresponding amines. The compound of formula V is an organic acid derivative or the organic acid having an alpha carbon atom and the compound of formula VI is an alkyl halide so that alkylation occurs at the alpha carbon atom of this carboxylic acid. This reaction is carried out by any conventional means of alkylation of the alpha carbon atom of a carboxylic acid or a lower alkyl ester of a carboxylic acid. Generally, in these alkylation reactions any alkyl halide is reacted with the anion generated from any acetic acid ester or the dianion of the acid. The anion can be generated by using a strong organic base such as lithium diisopropylamide, n-butyl lithium as well as other organic lithium bases. In carrying out this reaction, low boiling ether solvents are utilized such as tetrahydrofuran at low temperatures from xe2x88x9280xc2x0 C. to about xe2x88x9210xc2x0 C. being preferred. However any temperature from xe2x88x9280xc2x0 C. to room temperature can be used.
The compound of formula VII can be converted to the compound of formula XII by any conventional procedure to convert a carboxylic acid ester to an acid. The compound of formula XII is condensed with the compound of formula VIII via conventional peptide coupling to produce the compound of formula I-axe2x80x2. In carrying out this reaction, any conventional method of condensing a primary amine with a carboxylic acid can be utilized to effect this conversion. The required amino heteroaromatic compounds of formula VIII are commercially available or can be prepared from the reported literature. The heteroaromatics of formula VIII, wherein one of the substitutions is xe2x80x94(CH2)nCOOR6, where n=0, 1, 2, 3, or 4 can be prepared from the corresponding carboxylic acid. Any conventional carbon homologation methods to convert a lower carboxylic acid to its higher homologs, (see for example, Skeean, R. W.; Goel, O. P. Synthesis, 1990, 628) which then can be converted to the corresponding lower alkyl esters using any conventional esterification methods. The heteroaromatics of formula VIII, wherein one of the claimed substitutions is xe2x80x94(CH2)nOR7, where n=0, 1, 2, 3, or 4 can be prepared from the corresponding carboxylic acid. Any conventional carbon homologation methods to convert a lower carboxylic acid to its higher homologs, which then can be converted to the corresponding alcohols using any conventional ester reduction methods. The heteroaromatics of formula VIII, wherein one of the substituents is xe2x80x94C(O)C(O)OR7, or xe2x80x94C(O)xe2x80x94OR6, can be prepared from the corresponding halogen. Any conventional acylation method to convert an aromatic or heteroaromatic halogen to its oxoacetic acid lower ester or ester derivative (see for example, Hayakawa, K.; Yasukouchi, T.; Kanematsu, K. Tetrahedron Lett, 1987, 28, 5895) can be utilized.
The compound of formula VII has an asymmetric carbon atom through which the group xe2x80x94CH2R3 and the acid amide substituents are connected. In accordance with this invention, the preferred stereoconfiguration of this group is R.
If it is desired to produce the R or the S isomer of the compound of formula I, this compound can be separated into these isomers by any conventional chemical means. Among the preferred chemical means is to react the compound of formula XII with an optically active base. Any conventional optically active base can be utilized to carry out this resolution. Among the preferred optically active bases are the optically active amine bases such as alpha-methylbenzylamine, quinine, dehydroabietylamine and alpha-methylnaphthylamine. Any of the conventional techniques utilized in resolving organic acids with optically active organic amine bases can be utilized in carrying out this reaction.
In the resolution step, the compound of formula XII is reacted with the optically active base in an inert organic solvent medium to produce salts of the optically active amine with both the R and S isomers of the compound of formula XII. In the formation of these salts, temperatures and pressure are not critical and the salt formation can take place at room temperature and atmospheric pressure. The R and S salts can be separated by any conventional method such as fractional crystallization. After crystallization, each of the salts can be converted to the respective compounds of formula XII in the R and S configuration by hydrolysis with an acid. Among the preferred acids are dilute aqueous acids, i.e., from about 0.001N to 2N aqueous acids, such as aqueous sulfuric or aqueous hydrochloric acid. The configuration of formula XII which is produced by this method of resolution is carried out throughout the entire reaction scheme to produce the desired R or S isomer of formula I. The separation of R and S isomers can also be achieved using an enzymatic ester hydrolysis of any lower alkyl esters corresponding to the compound of the formula XII (see for example, Ahmar, M.; Girard, C.; Bloch, R, Tetrahedron Lett, 1989, 7053), which results in the formation of corresponding chiral acid and chiral ester. The ester and the acid can be separated by any conventional method of separating an acid from an ester. The preferred method of resolution of racemates of the compounds of the formula XII is via the formation of corresponding diastereomeric esters or amides. These diastereomeric esters or amides can be prepared by coupling the carboxylic acids of the formula XII with a chiral alcohol or a chiral amine. This reaction can be carried out using any conventional method of coupling a carboxylic acid with an alcohol or an amine. The corresponding diastereomers of compounds of the formula XII can then be separated using any conventional separation methods. The resulting pure diastereomeric esters or amides can then be hydrolyzed to yield the corresponding pure R or S isomers. The hydrolysis reaction can be carried out using conventional known methods to hydrolyze an ester or an amide without racemization.
All of the compounds of formula I which include the compounds set forth in the Examples activated glucokinase in vitro by the procedure of Example A. In this manner, they increase the flux of glucose metabolism which causes increased insulin secretion. Therefore, the compounds of formula I are glucokinase activators useful for increasing insulin secretion.
The following compounds were tested and found to have excellent glucokinase activator in vivo activity when administered orally in accordance with the assay described in Example B:
3-Cyclopentyl-2-(4-methanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide
3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethoxy-phenyl)-propionamide
3-Cyclopentyl-N-thiazol-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide
3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-pyridin-2-yl-propionamide
6-[3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionylamino]-nicotinic acid methyl ester
N-(5-Chloro-pyridin-2-yl)-3-cyclopentyl-2(R)-(3,4-dichloro-phenyl)-propionamide
3-Cyclopentyl-N-pyridin-2-yl-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide
3-Cyclopentyl-N-(5-methyl-pyridin-2-yl)-2-(4-trifluoromethanesulfonyl-phenyl)-propionamide
3-Cyclopentyl-2(R)-(3,4-dichloro-phenyl)-N-(5-hydroxymethyl-pyridin-2-yl)propionamide
6-[3-Cyclopentyl-2-(4-trifluoromethanesulfonyl-phenyl)-propionylamino]-nicotinic acid methyl ester
3-Cyclopentyl-2-(3-fluoro-4-trifluoromethyl-phenyl)-N-pyridin-2-yl-propionamide
3-Cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-N-pyridin-2-yl-propionamide
2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide
2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide
2-(4-Chloro-3-nitro-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyridin-2-yl-propionamide
N-(5-Bromo-pyridin-2-yl)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide
2-[3-Chloro-4-methanesulfonyl-phenyl]-3-cyclopentyl-N-thiazol-2-yl-propionamide
(2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide
2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
2-(3-Cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-thiazol-2-yl-propionamide
3-Cyclopentyl-2-(4-ethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide
3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-thiazol-2-yl-propionamide
N-(5-Bromo-pyridin-2-yl)-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide
3-Cyclopentyl-2-(4-methoxymethanesulfonyl-phenyl)-N-thiazol-2-yl-propionamide
3-Cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(4-methyl-thiazol-2-yl)-propionamide
3-Cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-N-(5-thethyl-thiazol-2-yl)-propionamide
N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2-(4-methanesulfonyl-phenyl)-propionamide
N-(5-Chloro-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide
N-(5-Bromo-thiazol-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-phenyl)-propionamide
2(R)-(3-Chloro-4-methanesulfony-phenyl)-3-cyclopentyl-N-(4-methyl-thiazol-2-yl)-propionamide
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-methyl-pyridin-2-yl)-propionamide
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide
2(R)-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide
2-(3-Chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrimidin-4-yl-propionamide
2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide
2-(3-Bromo-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-pyrazin-2-yl-propionamide
3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrimidin-4-yl-propionamide
3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-propionamide
3-Cyclopentyl-2-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide
3-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrimidin-4-yl-propionamide
3-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-pyrazin-2-yl-propionamide
3-Cyclopentyl-2(R)-(4-methanesulfonyl-3-trifluoromethyl-phenyl)-N-(2-methyl-pyrimidin-4-yl)-propionamide